Concept: An LXR agonist with high CNS penetrance, LXR-623, was tested for in vivo efficacy against GBMs.

Impact: LXR-623 is a potential therapy for patients with GBM and other brain cancers.

The blood–brain barrier (BBB) protects the internal microenvironment of the brain from systemic fluctuations in order to maintain normal brain homeostasis, which includes de novo cholesterol synthesis, for proper neural function. However, the BBB is also one of the major obstacles to the development of efficacious therapies for the treatment of brain tumors because it limits systemic drug delivery to intracranial tumors such as glioblastoma multiforme (GBM). Villa and colleagues, who had recently shown that activated EGFR signaling upregulates the expression of the cholesterol receptor low-density lipoprotein receptor in GBM cells, evaluated de novo cholesterol metabolism in GBM to ascertain whether GBMs exhibit a potentially exploitable dependency on exogenous cholesterol. GBM cells exhibited significantly decreased expression of the enzymes which drive de novo cholesterol synthesis and levels of oxysterols, which are oxidized cholesterol derivatives that bind to the liver X receptors (LXR) to induce the efflux of excess intracellular cholesterol, suggesting that LXR agonists may be efficacious against GBMs. The LXR agonist LXR-623, which had demonstrated favorable central nervous system (CNS) penetrance in a phase I trial, induced cell death in GBM cells and a breast cancer cell line derived from a brain metastasis but did not exhibit toxicity against normal human astrocytes. Consistent with these findings, systemic delivery of LXR-623 upregulated the expression of LXR target genes in normal cortex and induced cell death in various intracranial GBM xenograft models, including patient-derived xenografts, but not in peripheral tissues. Further, LXR-623 activated the beta isotype of LXR, which was the primary LXR isotype in GBM, resulting in the depletion of intracellular cholesterol in GBM cells. Taken together, these findings show that an activator of intracellular cholesterol efflux with high BBB penetrance and CNS selectivity is an efficacious therapy for GBM and potentially other types of brain cancer.